HIV is the leading cause of death among adults aged 15-64 in Africa. Recent wide-spread introduction of highly active antiretroviral therapy (HAART) to treat HIV in Africa has reduced mortality;however, mortality rates remain higher than in industrialized countries. In industrialized countries, HAART has lead to a shift in causes of death from acute opportunistic infections to chronic diseases. Causes of mortality on HAART and changes in specific risks over duration from HAART initiation are unknown in Africa. The proposed study will determine incidence and risks for mortality during HAART, changing factors associated with death over time, specific causes of death, and the role of both TB and hepatitis B in causal pathways to death. This data will be used to model the independent contributions of specific exposures such as HIV viremia, CD4 count, missed visits, and self initiated treatment interruption on death. These data will help to inform public health decisions regarding optimization of care guidelines and to prioritize potential interventions to reduce mortality. The proposed research will be conducted retrospectively within an ART cohort based in company HIV clinics in South Africa. The research will utilize 8 years of prospective follow-up in the ART cohort and routinely obtained autopsies, obtained for approximately 50% of workers who die. Marginal structural models will be used to assess causal inference for time varying covariates and effect modification will be assessed to identifying changing risks for death over time on HAART. This work builds on the PIs experience with research in Africa, longitudinal data analysis, and HIV outcomes. Completing this research in South Africa, along with structured mentorship and advanced statistics courses, will provide the necessary experience and guidance to develop skills and techniques needed for the PI to emerge as an independent investigator in the area of international HIV treatment. Careful description of long-term HAART outcomes and identification of risks for and causes of death is important to optimize treatment algorithms, develop prevention strategies, and implement cost-effective HIV care in Africa. Because of limited resources implementing a level of care as exists in industrialized countries is not feasible in most of Africa. However, the optimum approach to allocating resources to maximize outcomes is currently unclear. Knowledge of risks for and causes of mortality can contribute to informing resource allocation aimed at improving health and survival.